The New Techniques Driving Psychiatric Research

According to the World Health Organization, behavioural or mental patterns that distress or impair personal function challenge hundreds of millions of people globally. These patterns can manifest as psychiatric disorders like major depressive disorder, schizophrenia, or autism spectrum disorder (to name just a few), and their causes are the result of a complex interplay between biology and environmental factors, which differ from person to person.

Today, researchers are applying advanced molecular biology techniques directly to human brain tissue to investigate the underlying biology of psychiatric illness. The alternative is applying these types of techniques to model systems or model organisms. Mice, for example, can exhibit some depressive behaviours like anhedonia and sleep disturbances. Or, scientists can modify the mouse's genes to replicate symptoms of schizophrenia or autism spectrum disorder.

Using model organisms has advantages. For ethical reasons, it's often impossible to study biological mechanisms in people. In these cases, model organisms are the only choice. But there are also disadvantages: you miss out on the complexity of the human disease by studying aspects of it in isolation, and you can only model what you know. "It's important to look at these changes in humans as much as possible," says Dr. Corina Nagy, an assistant professor in the Department of Psychiatry at McGill University. "When talking about psychiatric disorders (...), as many animal models and in vitro models you generate, it's never going to truly reflect what is happening in humans."

Nagy uses single nucleus RNA sequencing to measure mRNA in cell nuclei isolated from the brains of people who passed away during an active bout of major depression. In a cell, active genes generate mRNA. mRNA then leads to a protein. And proteins determine the identity of a cell, how it functions, and how it interacts with other cells. By studying the mRNA from tens of thousands of nuclei in the brains of people with major depressive disorder and comparing it to people without the illness, you can learn how the brain cells are functioning and interacting differently.

Nagy and her colleagues published their findings using single nucleus RNA sequencing in 2020 in the journal Nature Neuroscience. In males with major depressive disorder, they found the majority of mRNA differences in two types of brain cells: oligodendrocyte precursor cells and deep layer excitatory neurons. Oligodendrocyte precursor cells, or OPCs, are so named because they are the cellular precursors to oligodendrocytes (the cells in the brain and spinal cord that generate myelin).

But, as Nagy and her colleagues point out in their 2020 paper, "OPCs are now thought to be a distinct [brain cell] type" with roles independent of their precursor function. They contribute to brain plasticity, for example. Excitatory neurons increase the likelihood of other neurons generating action potentials (the little bursts of electrical activity that serve as information currency in the brain). mRNA changes in OPCs and the excitatory neurons allowed the researchers to link the functioning of the two cell types. This link provides insight into how they interact with one another and how this changes with major depression.

Dr. Andrew Jaffe is an associate professor in the Departments of Mental Health, Biostatistics, Psychiatry and Behavioural Sciences, Neuroscience, and Human Genetics at John Hopkins University. Jaffe also studies mRNA changes in the brains of the deceased, but in a slightly different way. Spatial transcriptomics is a technique that allows you to measure mRNA in a way that preserves information about the precise location of where the mRNA came from.

Where a brain cell is located is related to its function. An OPC in the white matter tracts of the spinal cord may behave much differently than an OPC in the cerebellum, for example. Location is especially important in brain regions like the cortex, which has layers. Brain cells in each layer function differently, look different, work differently and connect differently.

Jaffe and his colleagues studied spatial mRNA changes in the six-layered human dorsolateral prefrontal cortex. The results were published in Nature Neuroscience in 2021. By integrating their spatial transcriptomic data with previously collected data about gene changes in psychiatric disorders, they localized genes implicated in schizophrenia and autism spectrum disorder to specific layers of the cortex.

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Using advanced techniques like single nuclei RNA sequencing and spatial transcriptomics to study psychiatric illness creates new opportunities for research. Nagy is using the technique to investigate sex differences in major depressive disorder. According to a 2013 systematic review published in Psychological Medicine, women are almost twice as likely to suffer from major depressive disorder than men. "The hypothesis is that cells (...) are being influenced differently in males and females," says Nagy. Nagy will also look at other areas of the brain associated with major depressive disorder like the limbic system.

Research like Nagy's and Jaffe's provides the foundation for better treatments. You're looking for a new target for drug discovery or testing existing drugs on the more nuanced molecular changes, says Jaffe. You want to get from single nucleotide polymorphism (a gene abnormality that increases the risk of getting a disease) to a difference in gene expression. If that expression is higher in disease, you can design an approach to alter it clinically.

Working directly with human brain tissue is not without its challenges. Human brain tissue available for research is limited and is incredibly hard to work with. Added is the complexity of the techniques, which require many different types of experts. The complexity has created a push for interdisciplinary or multidisciplinary research, says Jaffe. "Study teams now have a (...) molecular biologist, a strong computational person, and a clinician to interpret the output." But the challenges are worth overcoming in order to study a human illness in a human context. "One of the most important aspects of psychiatric research is to bring it back to the human entity," says Nagy.